US9376380B2ActiveUtilityPatentIndex 58
Cannabinoid receptor 2 (CB2) inverse agonists and therapeutic potential for multiple myeloma and osteoporosis bone diseases
Assignee: UNIV PITTSBURGH—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATIONPriority: Dec 15, 2011Filed: Jun 16, 2014Granted: Jun 28, 2016
Est. expiryDec 15, 2031(~5.4 yrs left)· nominal 20-yr term from priority
C07C 311/29C07C 233/40C07D 213/56C07C 233/36C07C 311/05C07C 311/48C07D 295/135C07C 311/20C07D 235/12C07C 311/18C07C 233/63C07C 69/78C07C 2101/14C07C 233/11C07C 2103/74C07C 233/13C07D 203/08C07D 211/06C07C 233/22C07C 233/78C07C 2603/74C07C 2601/14
58
PatentIndex Score
2
Cited by
31
References
17
Claims
Abstract
Cannabionid receptor-2 inverse antagonists include compounds represented by Formula IV, or a pharmaceutically acceptable salt thereof: wherein: R 1 and R 2 are independently H, alkyl, or alkenyl; R 3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R 4 and R 5 are independently a bond, alkylenyl, or alkenylenyl; each R 6 and R 7 is independently selected from the group consisting of OH, F, Cl, Br, I, (C 1 -C 6 )alkyl, alkoxy, amino, COOH, CONH 2 , SO 3 H, PO 3 H 2 , CN, SH, NO 2 and CF 3 ; and p and q are independently 0, 1, 2, 3, 4, or 5. Such compounds may be used to treat osteoporosis or multiple myeloma.
Claims
exact text as granted — not AI-modifiedWe claim:
1. A method for modulating the activity of a cannabinoid receptor-2(CB2) in a mammal in need thereof, comprising contacting the CB-2receptor with:
(a) a compound of Formula A′
wherein:
A is selected from the group consisting of —NR 2 , OR, (C 1 -C 6 )alkyl, and (C 3 -C 8 ) heterocycloalkyl;
R is selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 2 -C 6 ) alkenyl;
R′ is selected from the group consisting of sub-formula X, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, unsubstituted (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, adamantyl and C 6 H 4 R′″;
R″ is
wherein (i) l, m, n, p and q are each an integer 1, (ii) four of G, H, J, L and M are —CH and (iii) the remaining one of G, H, J, L and M is CR a ′″, or wherein (i) l, m and q are an integer 1, (ii) n is zero, (iii) p is an integer 2, and (iv) G, H and M are —CH and L is CR b ′″; and
R a ′″ is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , halogen, (C 1 -C 6 )haloalkoxy, and (C 1 -C 6 )alkoxy,
wherein when substituted (C 1 -C 6 )alkyl is present, the (C 1 -C 6 )alkyl is substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, heterocyclylalkoxy groups, carbonyl, ester, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, thiol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, amine, N-oxide, hydrazine, hydrazide, hydrazine, azide, amide, urea, amidine, guanidine, enamine, imide, isocyanate, isothiocyanate, cyanate, thiocyanate, imine, nitro group, and nitrile;
R b ′″ is an unsubstituted aryl;
wherein sub-formula X is represented by:
wherein Q′ is a bond or a (C 1 -C 6 )alkyl,
G, H, J, L, and M are each independently selected from the group consisting of a bond, CR′″—, —N—, —O—, and —S—, and no two adjacent members of G, H, J, L, or M can simultaneously be —O—, —S—, or N, and
represents the option of having one or more double bonds, or a pharmaceutically acceptable salt thereof; or (b) a compound of Formula B
wherein:
R is a (C 1 -C 6 )alkyl;
R′ is selected from the group consisting of (C 1 -C 7 )alkyl, adamantyl and C 6 H 4 R′′;
R″ is C 6 H 4 R′″; R′″ is selected from the group consisting of H, (C 1 -C 6 )alkyl, halogen, and (C 1 -C 6 )alkoxy, or a pharmaceutically acceptable salt thereof.
2. A method for modulating the activity of a cannabinoid receptor-2 (CB2) in a mammal in need thereof, comprising contacting the CB-2 receptor with a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is shown in the following table:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
3. The method according to claim 2 , wherein the compound is selected from the group consisting of Compounds 26-44, or a pharmaceutically acceptable salt thereof.
4. The method according to claim 2 , wherein the compound is selected from the group consisting of Compounds 14, 32 and 41, or a pharmaceutically acceptable salt thereof.
5. The method according to claim 3 , wherein the compound is Compound 41, or a pharmaceutically acceptable salt thereof.
6. The method according to claim 1 , wherein the mammal is a human.
7. The method according to claim 2 , wherein the mammal is a human.
8. The method according to claim 1 , wherein the compound is a compound of Formula A.
9. The method according to claim 1 , wherein the compound is a compound of Formula B.
10. The method of claim 8 , wherein A is —NR 2 and R is a (C 1 -C 6 )alkyl.
11. The method of claim 8 , wherein R″ is
wherein (i) l, m, n, p and q are each an integer 1, (ii) four of G, H, J. L and M are —CH, and (iii) the remaining one of G, H, J, L and M is CR a ′″, and R a ′″ is selected from the group consisting of H, halogen, (C 1 -C 6 )haloalkoxy, and (C 1 -C 6 )alkoxy.
12. The method of claim 2 , wherein the mammal suffers from multiple myeloma.
13. The method of claim 2 , wherein the mammal suffers from osteoporosis.
14. The method of claim 8 , wherein the mammal suffers from multiple myeloma.
15. The method of claim 8 , wherein the mammal suffers from osteoporosis.
16. The method of claim 9 , wherein the mammal suffers from multiple myeloma.
17. The method of claim 9 , wherein the mammal suffers from osteoporosis.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.